Medical devices brought into contact with blood (medical equipments and medical instruments) (more specifically, artificial kidneys, artificial lungs, artificial blood vessels, artificial valves, stents, stent-grafts, catheters, free-thrombus capture devices, angioscopes, sutures, blood circuits, tubes, cannulae, blood bags, syringes, and the like) are required to have high antithrombogenicity to prevent functional deterioration due to blood coagulation.
In particular, medical devices prepared with metallic materials such as stents are likely to be recognized as foreign substances by blood, and easily cause thrombus formation.
Methods in which an anticoagulant heparin or a heparin derivative is used for coating, or chemically binding to, a surface of a metallic material to give antithrombogenicity to the metallic material have been reported. Commonly known methods in which heparin or a heparin derivative is used for coating, or chemically binding to, a surface of a metallic material include 1) methods in which the heparin or heparin derivative is immobilized by covalent bonding to a functional group introduced to the surface of the metallic material; 2) methods in which an ionic complex is formed between an organic cation mixture and the heparin or heparin derivative, and the ionic complex is dissolved in an organic solvent, followed by coating the surface of the metallic material therewith; and 3) methods in which the heparin or heparin derivative is immobilized by ionic bonding to a positively charged cationic compound introduced to the surface of the metallic material.
Reported examples of the methods of 1) include a method in which aminated heparin is covalently bound to an ozone-treated surface of a metallic material through a coupling agent and a cross-linking agent (JP 3938418 B), and a method in which heparin is immobilized on a surface of a metallic material using a coating liquid containing heparin, dopamine, cross-linking activator, and cross-linking activity aid (JP 5576441 B).
Reported examples of the methods of 2) include a method in which an ionic complex is formed between an organic cation mixture such as a quaternary ammonium salt, and heparin or a heparin derivative, and the resulting ionic complex is dissolved in an organic solvent, followed by coating a surface of a metallic material with the resulting solution (JP 4273965 B).
Reported examples of the methods of 3) include a method in which amines composed of diaminocyclohexane are introduced to a surface of a metallic material by plasma treatment, and heparin is then immobilized to the introduced amines by ionic bonding (KR 2000-0059680 A).
A method in which a negatively charged, protein non-adsorptive substance such as heparin is bound to a surface of a base material to inhibit adsorption of cells to the surface has also been reported (JP 4982752 B).
However, in the methods disclosed in JP 3938418 B and JP 5576441 B, since the heparin or heparin derivative is immobilized on the surface of the metallic material by covalent bonding to a polymer or a low molecular weight compound, the degree of freedom of the heparin or heparin derivative is decreased. It is therefore difficult to obtain the anticoagulant activity required.
In the method disclosed in JP 4273965 B, an ionic complex is formed between an organic cation mixture such as a quaternary ammonium salt, and heparin or a heparin derivative, and the resulting ionic complex is dissolved in an organic solvent, followed by coating the surface of the metallic material with the resulting solution. This method does not allow uniform coating of the metallic material surface at present since highly hydrophilic portions of the ionic complex aggregate such that they are kept away from the organic solvent, causing phase separation in the drying step after the coating. Moreover, since elution of the organic cation mixture such as a quaternary ammonium salt easily occurs when it is brought into contact with a body fluid such as blood, the elution rate of the heparin or heparin derivative cannot be controlled.
Further, KR 2000-0059680 A describes a method in which a cationic compound having an amino group is introduced to a surface of a metallic material, and heparin, which is an anionic compound having anticoagulant activity, is bound to the cationic compound by ionic bonding to achieve its immobilization. However, there is no description on an appropriate amount of the heparin or heparin derivative to be introduced. Moreover, no study has been carried out on an appropriate amount of the cationic compound to be introduced to the surface of the metallic material. When the amount of the cationic compound for coating is too small, high antithrombogenicity cannot be obtained, while in cases where the amount is too large, the compound may exhibit hemolytic toxicity.
On the other hand, as described in JP 4982752 B, it is conventionally known that attachment of heparin or the like to a base material leads to a decrease in adhesiveness of cells to the surface of the base material. Thus, when an antithrombogenic material using heparin or the like is used for an artificial blood vessel, stent, stent-graft or the like, thrombosis can be prevented, but biological incorporation of the material by adhesion/growth of endothelial cells and the like may be inhibited.
It could therefore be helpful to provide an antithrombogenic metallic material that is highly safe with its low hemolytic toxicity, and capable of maintaining high antithrombogenicity for a long period.
It could also be helpful to provide an antithrombogenic metallic material that does not decrease adhesiveness of cells to the surface while the antithrombogenicity is maintained.